1. Field of the Invention
The present invention is concerned with novel N-substituted-17.beta.-carbamoylandrost-4-en-3-ones and their use as testosterone 5.alpha.-reductase inhibitors.
2. Description of the Prior Art
It is well known in the art that certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsuitism, and male pattern baldness, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone or similar androgenic hormones in the metabolic system. Early attempts to provide a chemotherapeutic agent to counter the undesirable results of hyperandrogenicity resulted in the discovery of several steroidal antiandrogens having undesirable hormonal activities of their own. The estrogens, for example, not only counteract the effect of the androgens but have a feminizing effect as well. Nonsteroidal antiandrogens have also been developed, for example, 4'-nitro-3'-trifluoromethylisobutyranilide. See Neri et al., Endo., Vol. 91, No. 2 (1972). However, these products, though devoid of hormonal effects, are systemically active, competing with the natural androgens for receptor sites, and hence have a tendency to feminize a male host or the male fetus of a female host.
It more recently became known in the art that the principal mediator of androgenic activity in a target organ is 5.alpha.-dihydrotestosterone, a far more potent androgen than testosterone itself, and that it is formed locally in the target organ by the action of testosterone-5.alpha.-reductase. It therefore has been postulated and demonstrated that inhibitors of testosterone-5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation. Nayfeh et al., Steroids, 14, 269 (1969) demonstrated in vitro that methyl 4-androsten-3-one-17.beta.-carboxylate was a testosterone-5.alpha.-reductase inhibitor. Then Voight and Hsia, Endocrinology, 92, 1216 (1973), Canadian Pat. No. 970,692, demonstrated that the above ester and the parent free acid, 4-androsten-3-one-17.beta.-carboxylic acid are both active inhibitors of testosterone-5.alpha.-reductase in vitro. They further demonstrated that topical application of either testosterone or 5.alpha.-dihydrotestosterone caused enlargement of the female hamster flank organ, an androgen dependent sebaceous structure. However, concommitant administration of 4-androsten-3-one-17.beta.-carboxylic acid or its methyl ester inhibited the response elicited by testosterone but did not inhibit the response elicited by 5.alpha.-dihydrotes-tosterone. These results were interpreted as indicating that the compounds were antiandrogenic by virtue of their ability to inhibit testosterone-5.alpha.-reductase.
Attempts by applicants herein to confirm the findings of Voigt and Hsia have failed to demonstrate the same degree of antiandrogenic activity in the female flank organ protocol. Furthermore, the acid and ester of Voigt and Hsia have been shown by applicants to be ineffective in atrophying the male hamster flank organ. This test is a greater challenge for an antiandrogen in that the male flank organ is constantly being stimulated by endogenous testosterone and, therefore, 5.alpha.-dihydrotestosterone if the 5.alpha.-reductase system is operative.
Surprisingly, it has now been found that the novel compounds of this invention are potent inhibitors of testosterone-5.alpha.-reductase in vitro and that N,N-diethyl-17.beta.-carbamoylandrost-4-en-3-one applied topically will significantly atrophy the male hamster flank organ.
It has further been demonstrated that N,N-diethyl-17.beta.-carbamoylandrost-4-en-3-one at relatively high doses does not cause feminization of male fetuses whereas the non-steroidal antiandrogen, 4'-nitro-3'-trifluoromethylisobutyranilide, mentioned previously does cause feminization as determined by the anogenital distance in fetal rate.
In addition to the free acid and ester described above, the unsubstituted amide, 4-androsten-3-one-17.beta.-carboxamide is also a known compound, described in J. Org. Chem., 19, 1758 (1954). However, this compound is quite toxic on subcutaneous administration, whereas the compounds of the present invention have failed to demonstrate any signs of toxicity.
The novel compounds of the present invention are, therefore, potent antiandrogens by virtue of their ability to specifically inhibit testosterone-5.alpha.-reductase.